Two of the greatest threats to public health in the United States as we enter the next century are drug addiction and obesity. Annual deaths attributable to nicotine and alcohol dependence alone are estimated at 450,000. Moreover, the surgeon general has noted that .." after smoking, weight related conditions are the second leading cause of death in the U.S. resulting in about 300,000 lives lost each year..." These individuals are at greatly elevated risk for many disorders, such as heart disease, hypertension, and diabetes. While these two health issues do not appear related in terms of etiology or phenomenology, they share important commonalities. The neural circuits affected by rewarding drugs and presumed to be profoundly altered in addiction are the very pathways that control intake of our most vital natural reward, food. The neural system most clearly implicated in drug addiction con stitutes the ventral striaturn (includin nucleus accumbens) and its associated circuitry, a region that also subserves motivated behaviors, such as feeding, drinking, sexual behavior, and incentive learning. In order to develop successful treatments for addiction and eating disorders, it is necessary to further understand the biological mechanisms underlying motivation. Specifically, it would be useful to investigate in detail the neural mecahnisms underlying the hedonic aspects of eating ("food reward"). The research proposed here will address this question, integrating behavioral, pharmacological, anatomical and molecular biological (in situ hybridization) techniques. The main hypothesis that guides the proposed experiments is that opioid systems, particularly in the ventral striaturn, play a critical role in an animal's affective response to food; that is in the "liking" process, or the orosensory pleasure derived from highly palatable foods. It is further proposed that the ventral striaturn is a key brain region where peripheral metabolic neurohumoral signals are integrated with central control of motivational states and adaptive responding. In these experiments, we will analyze the role of signal transduction pathways, enkephalin gene expression, and circulating insulin in opioid-mediated feeding, and will also examine organization of underlying circuitries that may be involved in processing of palatability signals.